1024-Pixel CMOS Multimodality Joint Cellular Sensor/Stimulator Array for Real-Time Holistic Cellular Characterization and Cell-Based Drug Screening

Park, Jong Seok; Aziz, Moez Karim; Li, Sensen; Chi, Taiyun; Grijalva, Sandra I.; Sung, Jung Hoon; Cho, Hee Cheol; Wang, Hua

doi:10.1109/tbcas.2017.2759220

Cited by 48 publications

(25 citation statements)

References 64 publications

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“…The limitations of the single-cell amperometry can be overcome by using a scalable CMOS device in which the electrodes are each directly integrated with a dedicated amplifier. Several CMOS-based monolithic biosensors have been proposed using this concept of monolithic integration [8]–[13] to perform various types of electrophysiology with enhanced spatiotemporal resolution. A device that was proposed for the application of DNA sequencing integrated a solid-state nanopore onto a CMOS chip and achieved enhanced temporal resolution as well as low noise performance with a sampling rate of up to 20 MHz [9], [14].…”

Section: Introductionmentioning

confidence: 99%

“…To study bursting events from neurons in a neuronal network, a device providing high spatial resolution with an array of 4096 electrodes was proposed [18]. Another proposed system contains 1024 pixels to provide a low-noise multifunctional CMOS device with enhanced spatiotemporal resolution for extracellular potential measurement, optical cell detection, current stimulation, and cellular impedance measuring [13]. A low-noise device with an integrated on-chip electrode array was developed for the purpose of parallel recording of neurotransmitter release with a channel count of 100, providing high-throughput amperometric measurements [8].…”

Section: Introductionmentioning

confidence: 99%

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Single-Cell Recording of Vesicle Release From Human Neuroblastoma Cells Using 1024-ch Monolithic CMOS Bioelectronics

White

Mulberry

Smith

et al. 2018

IEEE Trans. Biomed. Circuits Syst.

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Human neuroblastoma cells, SH-SY5Y, are often used as a neuronal model to study Parkinson’s disease and dopamine release in the substantia nigra, a midbrain region that plays an important role in motor control. Using amperometric single-cell recordings of single vesicle release events, we can study molecular manipulations of dopamine release and gain a better understanding of the mechanisms of neurological diseases. However, single-cell analysis of neurotransmitter release using traditional techniques yields results with very low throughput. In this paper, we will discuss a monolithically-integrated CMOS sensor array that has the low-noise performance, fine temporal resolution, and 1024 parallel channels to observe dopamine release from many single cells with single-vesicle resolution. The measured noise levels of our transimpedance amplifier are 415, 622, and 1083 fARMS , at sampling rates of 10, 20, and 30 kS/s, respectively, without additional filtering. Post-CMOS processing is used to monolithically integrate 1024 on-chip gold electrodes, with an individual electrode size of 15 μm × 15 μm, directly on 1024 transimpedance amplifiers in the CMOS device. SU-8 traps are fabricated on individual electrodes to allow single cells to be interrogated and to reject multicellular clumps. Dopamine secretions from 76 cells are simultaneously recorded by loading the CMOS device with SH-SY5Y cells. In the 42-second measurement, a total of 7147 single vesicle release events are monitored. The study shows the CMOS device’s capability of recording vesicle secretion at a single-cell level, with 1024 parallel channels, to provide detailed information on the dynamics of dopamine release at a single-vesicle resolution.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Single-Cell Recording of Vesicle Release From Human Neuroblastoma Cells Using 1024-ch Monolithic CMOS Bioelectronics

White

Mulberry

Smith

et al. 2018

IEEE Trans. Biomed. Circuits Syst.

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“…Neonatal rat ventricular myocytes (NRVMs) and cardiac fibroblasts are isolated from 1 to 2 day-old neonatal rats and cultured as monolayers as previously described. 45,[71][72][73] NRVMs are transduced with an Ad-GFP vector (MOI = 1-2) for 2 hours in suspension at room temperature (RT) and then seeded overnight on the CMOS chip. NRVM spheroids are formed using AggreWellTM (STEMCELL, Vancouver, Canada).…”

Section: Neonatal Rat Ventricular Myocyte and Fibroblast On-chip Culturementioning

confidence: 99%

“…The detailed operations of the CMOS chip, its electrical characterization, and the biocompatible packaging techniques are explained in references. 44 , 45 Fibroblasts and neonatal rat ventricular myocytes (NRVM) are successfully cultured on-chip. The time-lapse cell transparency/density and cell-to-surface adhesion of the on-chip cultured fibroblasts are measured by two distinct sensing modalities: static optical opacity detection and cellular impedance characterization.…”

Section: Introductionmentioning

confidence: 99%

Multi-parametric cell profiling with a CMOS quad-modality cellular interfacing array for label-free fully automated drug screening

et al. 2018

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Cells are complex systems with concurrent multi-physical responses, and cell physiological signals are often encoded with spatiotemporal dynamics and further coupled with multiple cellular activities. However, most existing electronic sensors are only single-modality and cannot capture multi-parametric cellular responses. In this paper, a 1024-pixel CMOS quad-modality cellular interfacing array that enables multi-parametric cell profiling for drug development is presented. The quad-modality CMOS array features cellular impedance characterization, optical detection, extracellular potential recording, and biphasic current stimulation. The fibroblast transparency and surface adhesion are jointly monitored by cellular impedance and optical sensing modalities for comprehensive cell growth evaluation. Simultaneous current stimulation and opto-mechanical monitoring based on cardiomyocytes are demonstrated without any stimulation/sensing dead-zone. Furthermore, drug dose-dependent multi-parametric feature extractions in cardiomyocytes from their extracellular potentials and opto-mechanical signals are presented. The CMOS array demonstrates great potential for fully automated drug screening and drug safety assessments, which may substantially reduce the drug screening time and cost in future new drug development.

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“…The here presented CMOS MEA chip includes the largest number of operating modalities if compared with other MEA chips present in the literature and commercially available (Lopez et al, 2018). Moreover, the electrode pitch is only 15 μm thus allowing for higher electrode densities and single cell resolution if compared with other reported devices (Abbott et al, 2017; Park et al, 2018a; Tsai et al, 2018). Besides this, the fabrication process, including the electrode, is fully CMOS compatible, and thus allows for reproducible manufacturing conditions.…”

Section: Introductionmentioning

confidence: 97%

High-Density Electrical Recording and Impedance Imaging With a Multi-Modal CMOS Multi-Electrode Array Chip

et al. 2019

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Multi-electrode arrays, both active or passive, emerged as ideal technologies to unveil intricated electrophysiological dynamics of cells and tissues. Active MEAs, designed using complementary metal oxide semiconductor technology (CMOS), stand over passive devices thanks to the possibility of achieving single-cell resolution, the reduced electrode size, the reduced crosstalk and the higher functionality and portability. Nevertheless, most of the reported CMOS MEA systems mainly rely on a single operational modality, which strongly hampers the applicability range of a single device. This can be a limiting factor considering that most biological and electrophysiological dynamics are often based on the synergy of multiple and complex mechanisms acting from different angles on the same phenomena. Here, we designed a CMOS MEA chip with 16,384 titanium nitride electrodes, 6 independent operational modalities and 1,024 parallel recording channels for neuro-electrophysiological studies. Sixteen independent active areas are patterned on the chip surface forming a 4 × 4 matrix, each one including 1,024 electrodes. Electrodes of four different sizes are present on the chip surface, ranging from 2.5 × 3.5 μm 2 up to 11 × 11.0 μm 2 , with 15 μm pitch. In this paper, we exploited the impedance monitoring and voltage recording modalities not only to monitor the growth and development of primary rat hippocampal neurons, but also to assess their electrophysiological activity over time showing a mean spike amplitude of 144.8 ± 84.6 μV. Fixed frequency (1 kHz) and high sampling rate (30 kHz) impedance measurements were used to evaluate the cellular adhesion and growth on the chip surface. Thanks to the high-density configuration of the electrodes, as well as their dimension and pitch, the chip can appreciate the evolutions of the cell culture morphology starting from the moment of the seeding up to mature culture conditions. The measurements were confirmed by fluorescent staining. The effect of the different electrode sizes on the spike amplitudes and noise were also discussed. The multi-modality of the presented CMOS MEA allows for the simultaneous assessment of different physiological properties of the cultured neurons. Therefore, it can pave the way both to answer complex fundamental neuroscience questions as well as to aid the current drug-development paradigm.

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1024-Pixel CMOS Multimodality Joint Cellular Sensor/Stimulator Array for Real-Time Holistic Cellular Characterization and Cell-Based Drug Screening

Cited by 48 publications

References 64 publications

Single-Cell Recording of Vesicle Release From Human Neuroblastoma Cells Using 1024-ch Monolithic CMOS Bioelectronics

Single-Cell Recording of Vesicle Release From Human Neuroblastoma Cells Using 1024-ch Monolithic CMOS Bioelectronics

Multi-parametric cell profiling with a CMOS quad-modality cellular interfacing array for label-free fully automated drug screening

High-Density Electrical Recording and Impedance Imaging With a Multi-Modal CMOS Multi-Electrode Array Chip

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